The full potential of chemotherapy can be limited in practice by toxic side effects. Therefore, strategies or interventions that are effective in selectively protecting normal cells, but not cancer cells, are predicted to increase the therapeutic window and clinical effectiveness of chemotherapy. Published literature demonstrates that mice subjected to short-term starvation are protected from high doses of etoposide that kill their fed littermates. In addition, tumor cells carrying mutations that cause constitutive activation of the PI3K pathway have been shown to be insensitive to the anti-growth effects of dietary restriction when grown as xenografts in mice. Thus, fasting may enhance the effectiveness of chemotherapy by protecting normal cells, but not cancer cells, from the toxic effects of chemotherapy and clinical trials are currently being conducted to test whether fasting prior to or during chemotherapy reduces associated side-effects in cancer patients. However, little is known about the molecular mechanisms mediating the differential response of normal cells compared with cancer cells to short-term starvation. Using a reporter mouse engineered to express firefly luciferase from the endogenous p21 promoter, we observe a potent induction of p21 expression in response to short-term starvation. Interestingly, this occurs in metabolic organs and p21 expression was also observed, for the first time, in particular neurons ofthe hypothalamus that regulate metabolism. Our preliminary studies also demonstrate that p21 protects cells from the DNA damaging effects of irinotecan, a topoisomerase 1 inhibitor used clinically to treat certain types of cancer. Thus, experiments proposed in this application will (1) determine if induction of p21 expression by short-term starvation protects mice from the lethal effects of high dose chemotherapy and ionizing radiation, (2) identify the signaling pathway(s) responsible for activating p21 expression in response to short-term starvation and (3) determine if short-term starvation protects mice, but not PTEN-deficient prostate cancers growing in these mice, from chemotherapy and radiation therapy.